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A Promising Future for Stem-Cell-Based Therapies in Muscular Dystrophies—In Vitro and in Vivo Treatments to Boost Cellular Engraftment

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A Promising Future for Stem-Cell-Based Therapies in Muscular Dystrophies—In Vitro and in Vivo Treatments to Boost Cellular Engraftment International Journal of Molecular Sciences Review A Promising Future for Stem-Cell-Based Therapies in Muscular Dystrophies—In Vitro and In Vivo Treatments to Boost Cellular Engraftment Daniela Gois Beghini 1, Samuel Iwao Horita 1, Liana Monteiro da Fonseca Cardoso 2, Luiz Anastacio Alves 2, Kanneboyina Nagaraju 3 and Andrea Henriques-Pons 1,* 1 Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro (RJ) 21040-900, Brazil; beghini@ioc.fiocruz.br (D.G.B.); samuel.horita@ioc.fiocruz.br (S.I.H.) 2 Laboratório de Comunicação Celular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro (RJ) 21040-900, Brazil; [email protected] (L.M.d.F.C.); [email protected] (L.A.A.) 3 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, New York, NY 13902, USA; [email protected] * Correspondence: andreah@ioc.fiocruz.br; Tel.: +55-21-2562-1319 Received: 9 June 2019; Accepted: 23 September 2019; Published: 31 October 2019 Abstract: Muscular dystrophies (MD) are a group of genetic diseases that lead to skeletal muscle wasting and may affect many organs (multisystem). Unfortunately, no curative therapies are available at present for MD patients, and current treatments mainly address the symptoms. Thus, stem-cell-based therapies may present hope for improvement of life quality and expectancy. Different stem cell types lead to skeletal muscle regeneration and they have potential to be used for cellular therapies, although with several limitations. In this review, we propose a combination of genetic, biochemical, and cell culture treatments to correct pathogenic genetic alterations and to increase proliferation, dispersion, fusion, and differentiation into new or hybrid myotubes. These boosted stem cells can also be injected into pretreate recipient muscles to improve engraftment. We believe that this combination of treatments targeting the limitations of stem-cell-based therapies may result in safer and more efficient therapies for MD patients. Matricryptins have also discussed. Keywords: muscular dystrophy; stem cells therapy; muscle regeneration; matricryptins and matrikines; inflammation 1. Muscular Dystrophies Muscular dystrophies (MDs) are genetic disorders caused by mutations in several genes that lead to the lack of or dysfunctional production of proteins that are essential for myofiber integrity and contraction. MDs are a group of diseases that cause, but are not restricted to, progressive muscle destruction and weakness, with nine most common forms: myotonic, Duchenne, Becker, limb-girdle, facioscapulohumeral, congenital, oculopharyngeal, distal, and Emery–Dreifuss. Each disorder varies significantly in severity, pattern of inheritance, age of onset, affected gender, targeted muscles and other organs, levels of muscle damage, etc. (summary in Supplementary Table S1). The approximate combined prevalence of all MDs ranges between 19.8 and 25.1 per 100,000 people/year, a very high incidence of debilitating diseases that affect social integration and life expectancy [1]. For a conclusive diagnosis, it is essential to observe medical and family history, including the distribution of weakness in different muscles and the age of onset, gene sequencing, laboratory investigations, electromyography, and muscle biopsy. Prognosis is also highly variable across MD patients, varying from mild to severe disability and early death, usually with the progressive development of symptoms. Comprehension of MD pathophysiology has increased considerably in the last decade, but there remains no cure. Current Int. J. Mol. Sci. 2019, 20, 5433; doi:10.3390/ijms20215433 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 5433 2 of 26 treatments, in general, aim to manage and slow the progression of symptoms, which reinforces the need for new therapies to increase patients’ life expectancy and quality of life. In this review, we have summarized the most common forms of MD and the therapies available. However, most patients receive only palliative therapeutic strategies that aim to alleviate the symptoms, with no effective treatments. Although stem-cell-based therapies offer hope for these patients, they have many limitations. Stem cells usually have a limited capacity to engraft muscles due, for example, to reduced cellular viability, dispersion, proliferation, and differentiation to myotubes. Many of these limitations have been individually addressed in the literature, and there are biochemical, genetic, and in vitro culture approaches that can improve cellular engraftment. Here, we have summarized these studies and propose combined treatments for stem cells and their recipient muscles, aiming to prolong the survival of grafted cells and promote sustained, healthy myotube formation. Although not yet tested in muscle stem cells, matricryptins are nontoxic, bioactive peptides that induce tumor cell survival, migration, proliferation, and differentiation, all desired biological responses for muscle stem cells. These molecules are possible boosts that could be used in combination with other stimuli for stimulating stem cells in muscle therapy. The broad spectrum of pathogenic genetic defects and clinical symptoms suggests that different combinations of boosts may be required for different MDs. 1.1. Myotonic Muscular Dystrophy (MMD) Myotonic muscular dystrophy (MMD) is a dominant, autosomal disease with two similar but distinct forms, type 1 (MMD1) and 2 (MMD2). MMD1 is also named Steinert’s Disease, in honor of the scientist who first described the disease in 1909. MMD2 was first described more recently thanks to genetic testing becoming available for clinical practice. MMD1 is the most common form of the disease and is found in adults, although a late onset is not a rule. The symptoms include muscle weakness and wasting, cardiac conduction defects, myotonia, diabetes and insulin resistance, cataracts, and many others, leading to multisystem involvement. MMD1 can be divided into four different forms according to clinical phenotype, illustrating the broad range of symptoms and general characteristics [2]. In adult-onset MMD, diagnostic efforts are usually initiated because of muscle weakness, myotonia, or cataracts—the three main symptoms. In this case, a family history of type 1 MDD combined with minor symptoms is a common starting point in diagnostic examination. The progression of the disease is slow and advances to deepened skeletal muscle weakness, including the face, neck, and distal limb muscles; eventual immobility; respiratory insufficiency; dysarthria; and dysphagia. The latter is one of the leading causes of severe disability and death in the late stages of adult-onset MMD1. The cardiac muscle shows conduction defects and tachyarrhythmia, most likely due to fibrosis. Usually, the detection of cataracts in older patients does not initiate further diagnostic considerations for MMD1, but should particularly alert clinicians when detected in patients under the age of 50 and associated with specific structural characteristics [3]. The central nervous system can also be affected, leading to progressive cognitive impairment and late apathy [4], as well as gastrointestinal disorders such as constipation, incontinence, and diarrhea [5]. Endocrine dysfunction is also found, leading mostly to insulin resistance and susceptibility to diabetes, hypothyroidism, male hypogonadism, and adrenal insufficiency [6]. The second form of MMD1 is Congenital MMD; this is the most severe form of MMD, and is usually detected prenatally because of reduced fetal movements and different deformities. At birth, babies have severe hypotonia in their limb, trunk, respiratory, facial, and bulbar muscles, leading to respiratory dysfunction and feeding difficulties [7]. Mental retardation can also be observed. In childhood-onset MMD, there is no myotonia or muscle weakness, which imposes challenges for MD diagnosis and correct assistance. Instead, children have delayed learning at school and show signs of mental retardation. These patients also develop muscle weakness and wasting at an older age, causing physical disabilities comparable with severe adult-onset type 1 disease [8]. Finally, in late-onset oligosymptomatic MMD, the genetic family history is significant for clinicians considering a MMD diagnosis, as mild symptoms can be observed in earlier generations, like cataracts Int. J. Mol. Sci. 2019, 20, 5433 3 of 26 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 27 andgenerations, discrete like muscle cataracts weakness. and discrete However, muscle later weakness. generations However, can have later severe generations disease can characteristics, have severe includingdisease characteristics, muscle wasting including and atrophy, muscle cataracts, wasting andand othersatrophy, [2]. cataracts, and others [2]. TheThe broadbroad spectrum spectrum of of tissues tissues and and organs organs affected, affect noted, restrictednot restricted solely solely to muscles, to muscles, and the and disease the severitydisease inseverity MMD1 in is MMD1 determined is determined by the underlying by the molecularunderlying pathogenesis molecular pathogenesis which is mediated which byis deleteriousmediated by nuclear deleterious RNA nuclear repeats. RNA Therefore, repeats. abnormalities Therefore, abnormalities in many pathways in many of RNApathways metabolism, of RNA includingmetabolism, alternative including splicing, alternative can splicing, be detected can inbe MMD1.detected Inin healthyMMD1. cells,In healthy pre-mRNA
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